Expression of Wild-Type and Mutant Human TDP-43 in Yeast Inhibits TOROID (TORC1 Organized in Inhibited Domain) Formation and Autophagy Proportionally to the Levels of TDP-43 Toxicity.

TDP-43 forms aggregates in the neurons of patients with several neurodegenerative diseases. Human TDP-43 also aggregates and is toxic in yeast. Here, we used a yeast model to investigate (1) the nature of TDP-43 aggregates and (2) the mechanism of TDP-43 toxicity. Thioflavin T, which stains amyloid but not wild-type TDP-43 aggregates, also did not stain mutant TDP-43 aggregates made from TDP-43 with intragenic mutations that increase or decrease its toxicity. However, 1,6-hexanediol, which dissolves liquid droplets, dissolved wild-type or mutant TDP-43 aggregates. To investigate the mechanism of TDP-43 toxicity, the effects of TDP-43 mutations on the autophagy of the GFP-ATG8 reporter were examined. Mutations in TDP-43 that enhance its toxicity, but not mutations that reduce its toxicity, caused a larger reduction in autophagy. TOROID formation, which enhances autophagy, was scored as GFP-TOR1 aggregation. TDP-43 inhibited TOROID formation. TORC1 bound to both toxic and non-toxic TDP-43, and to TDP-43, with reduced toxicity due to pbp1Δ. However, extragenic modifiers and TDP-43 mutants that reduced TDP-43 toxicity, but not TDP-43 mutants that enhanced toxicity, restored TOROID formation. This is consistent with the hypothesis that TDP-43 is toxic in yeast because it reduces TOROID formation, causing the inhibition of autophagy. Whether TDP-43 exerts a similar effect in higher cells remains to be determined.

Four-hour-delayed 3D-FLAIR MRIs in patients with acute unilateral peripheral vestibulopathy.

OBJECTIVE: Conventionally, MRI aids in differentiating acute unilateral peripheral vestibulopathy/vestibular neuritis (AUPV/VN) from mimickers. Meanwhile, the diagnostic utility of MRIs dedicated to the inner ear remains to be elucidated for diagnosing AUPV/VN. METHODS: We prospectively recruited 53 patients with AUPV/VN (mean age ± SD = 60 ± 15 years, 29 men). Initial MRIs were performed with a standard protocol, and an additional axial 3D-fluid-attenuated inversion recovery (3D-FLAIR) sequence was obtained 4 h after intravenous injection of gadoterate meglumine. Abnormal enhancement was defined as a signal intensity that exceeded the mean + 2SD value on the healthy side. The findings of neurotologic evaluation and MRIs were compared. RESULTS: Overall, the inter-rater agreement for gadolinium enhancement was 0.886 (Cohen's kappa coefficient). Enhancement was observed in 26 patients (49%), most frequently in the vestibule (n = 20), followed by the anterior (n = 12), horizontal (HC, n = 8), posterior canal (n = 5), and superior (n = 3) and inferior (n = 1) vestibular nerves. In multivariable logistic regression analysis, the enhancement was associated with decreased HC gain in video head-impulse tests (p = 0.036), increased interaural difference in ocular vestibular-evoked myogenic potentials (p = 0.001), and a longer onset-to-MRI time span (p = 0.024). The sensitivity and specificity were 92.3% and 81.5%, respectively, with an area under the curve of 0.90 for predicting gadolinium enhancement. INTERPRETATION: Robust gadolinium enhancement was observed on 4-hour-delayed 3D-FLAIR images in nearly half of the patients with AUPV/VN, with a good correlation with the results of neurotologic evaluation. The positivity may be determined by the extent of vestibular deficit, timing of imaging acquisition, and possibly by the underlying etiology causing AUPV/VN. MRIs may aid in delineating the involved structures in AUPV/VN.

Ultrasound biomicroscopy analysis of ciliary muscle dynamics and its relation to intra-ocular pressure after phacoemulsification in dogs.

Introduction: This study investigates the relationship between ciliary muscle dynamics, thickness, and the regulation of intraocular pressure (IOP), focusing on the progression of cataracts and changes post-phacoemulsification. It explores how these factors impact canine ocular health, particularly in the context of cataract development and subsequent surgical intervention. Materials and methods: Data was collected using Ultrasound Biomicroscopy (UBM) from dogs at the Veterinary Medical Teaching Hospital of Chungbuk National University, Korea. The study involved 57 eyes from 35 dogs, categorized into five groups: 13 normal eyes, 14 with incipient cataracts, 12 with immature cataracts, 6 with mature cataracts, and 12 post-phacoemulsification. UBM measurements assessed various ciliary muscle parameters including ciliary body axial length (CBAXL), ciliary process-sclera angle (CPSA), longitudinal fibers of ciliary muscle thickness (Lf-CMT), and longitudinal and radial fibers of ciliary muscle thickness (LRf-CMT). Results: Findings indicated a decrease in CBAXL and an increase in Lf-CMT as cataracts progressed in severity. Post-phacoemulsification, there was a notable increase in CBAXL and a decrease in CPSA, Lf-CMT, and LRf-CMT, compared to both cataractous and normal eyes. Regression analysis revealed a significant positive association between CBAXL and IOP, alongside a negative association between Lf-CMT and IOP. These findings suggest that variations in ciliary muscle dynamics and thickness, as influenced by cataract progression and phacoemulsification, have distinct impacts on intraocular pressure. Discussion: The study proposes that phacoemulsification leads to ciliary muscle contraction, causing an inward and anterior movement of the ciliary muscle. This movement results in the narrowing of the ciliary cleft and constriction of the unconventional outflow pathway, potentially causing an increased risk of glaucoma post-surgery. Our research contributes to understanding the anatomical and physiological changes in the canine eye following cataract surgery and underscores the importance of monitoring IOP and ciliary muscle dynamics in these patients.

Arthroscopic cuff repair: footprint remnant preserving versus debriding rotator cuff repair of transtendinous rotator cuff tears with remnant cuff.

BACKGROUND: In transtendinous full thickness rotator cuff tears (FTRCT) with remnant cuff, conventionally, cuff remnant of the greater tuberosity (GT) is debrided for better tendon to bone healing. However, larger cuff defect caused overtension on the repaired tendon. The purpose of this study was to compare the clinical outcomes and tendon integrity between remnant preserving and remnant debriding cuff repairs in the transtendinous FTRCT with remnant cuff. METHODS: From March, 2012 to October, 2017, a total of 127 patients who had the transtendinous FTRCT with remnant cuff were enrolled in this study. Rotator cuff tears were repaired arthroscopically, with patients divided into two groups: group I (n = 63), where rotator cuff remnants were preserved during the repair, and group II (n = 64), where the remnants were debrided during the repair. Clinical outcomes were assessed at the last follow-up (minimum 2 years) using the UCLA score, ASES score, SST score, Constant Shoulder score, and range of motion (ROM). The analysis of structural integrity and tendon quality was performed using the Sugaya classification on postoperative MRI scans at 8 months after surgery. RESULTS: At the final follow-up, UCLA, ASES, SST, and CS scores significantly improved from preoperative values to postoperative (all p < 0.05): UCLA (I: 19.6 ± 6.0 to 31.7 ± 3.2, II: 18.0 ± 5.7 to 31.5 ± 3.2), ASES (I: 54.3 ± 10.7 to 86.5 ± 12.5, II: 18.0 ± 5.7 to 85.8 ± 12.4), SST (I: 5.6 ± 2.8 to 10.2 ± 2.0, II: 5.0 ± 2.9 to 10.1 ± 2.5), CS (I: 74.0 ± 17.2 to 87.8 ± 9.7, II: 62.0 ± 19.2 to 88.3 ± 6.2). However, there were no significant differences between the two groups (p > 0.05). Also, remnant preserving cuff repair yielded significantly better tendon quality on postoperative MRI (p < 0.05). The incidence of re-tear (Sugaya's Type IV and V) was not significantly different between the two groups (I:17% vs. II:19%; p = 0.053). CONCLUSIONS: Remnant preserving rotator cuff repairs, which facilitate tendon-to-tendon healing, are superior in terms of tendon quality and are the preferred option for transtendinous FTRCT. TRIAL REGISTRATION: Retrospectively registered.

Molecular detection and characterization of Acanthamoeba infection in dogs and its association with keratitis in Korea.

Acanthamoeba infection is associated with keratitis in humans; however, its association with keratitis in dogs remains unclear. To investigate this possibility, we collected 171 conjunctival swab samples from dogs with eye-related diseases (65 with keratitis and 106 without keratitis) at Chungbuk National University Veterinary Teaching Hospital, Korea, from August 2021 to September 2022. Polymerase chain reaction identified 9 samples (5.3%) as Acanthamoeba positive; of these, 3 were from dogs with keratitis (4.6%) and 6 were from dogs without keratitis (5.7%). Our results indicated no significant association between Acanthamoeba infection and keratitis, season, sex, or age. All Acanthamoeba organisms found in this study had the genotype T4, according to 18S ribosomal RNA analysis. Acanthamoeba infection in dogs might have only a limited association with keratitis.

Discovery of N-benzylbenzamide-based allosteric inhibitors of Aurora kinase A.

Aurora kinases (AurkA/B/C) regulate the assembly of bipolar mitotic spindles and the fidelity of chromosome segregation during mitosis, and are attractive therapeutic targets for cancers. Numerous ATP-competitive AurkA inhibitors have been developed as potential anti-cancer agents. Recently, a few allosteric inhibitors have been reported that bind to the allosteric Y-pocket within AurkA kinase domain and disrupt the interaction between AurkA and its activator TPX2. Herein we report a novel allosteric AurkA inhibitor (6h) of N-benzylbenzamide backbone. Compound 6h suppressed the both catalytic activity and non-catalytic functions of AurkA. The inhibitory activity of 6h against AurkA (IC50 = 6.50 µM) was comparable to that of the most potent allosteric AurkA inhibitor AurkinA. Docking analysis against the Y-pocket revealed important pharmacophores and interactions that were coherent with structure-activity relationship. In addition, 6h suppressed DNA replication in G1-S phase, which is a feature of allosteric inhibition of AurA. Our current study may provide a useful insight in designing potent allosteric AurkA inhibitors.

Tri-component hydrocolloid as egg white replacement in meringues: gellan gum with soy protein isolate and maltodextrin.

BACKGROUND: In the quest for sustainable food ingredients, the present study delves into the potential of a tri-component hydrocolloid blend, comprising gellan gum (GG), soy protein isolate (SPI) and maltodextrin (MD), as a replacement for egg white in meringue production. The research aims to elucidate the intricate physical properties of meringue containing this tri-component structure, focusing on foaming dynamics, rheological behavior and the textural properties of the resulting meringue cookies. RESULTS: Experiments were conducted with various hydrocolloids (k-carrageenan, GG, and locust bean gum) and GG was identified as optimal for improving foaming capacity and foaming stability. Rheological evaluations showed a positive correlation between increased GG concentration within the tri-component matrix and an increase in both storage modulus (G') and loss modulus (G"), indicating improved structural integrity. Furthermore, a comparative analysis of the texture profiles of cookies prepared with this blend highlighted the ability of higher GG concentrations to satisfactorily replicate the tactile and visual qualities of traditional egg white-based meringues. This result was particularly evident compared to formulations utilizing solely SPI or the combined SPI-MD configuration. CONCLUSION: Conclusively, the results of the present study highlight the significant potential of the GG-SPI-MD tri-component structure to closely mimic the critical properties of egg white, thus offering a promising plant-based alternative for meringue production. © 2024 Society of Chemical Industry.

Beneficial Effect of Sirolimus-Pretreated Mesenchymal Stem Cell Implantation on Diabetic Retinopathy in Rats.

BACKGROUND: Diabetic retinopathy (DR) is a vision-threatening complication that affects virtually all diabetic patients. Various treatments have been attempted, but they have many side effects and limitations. Alternatively, stem cell therapy is being actively researched, but it faces challenges due to a low cell survival rate. In this study, stem cells were pretreated with sirolimus, which is known to promote cell differentiation and enhance the survival rate. Additionally, the subconjunctival route was employed to reduce complications following intravitreal injections. METHODS: Diabetes mellitus was induced by intraperitoneal injection of 55 mg/kg of streptozotocin (STZ), and DR was confirmed at 10 weeks after DM induction through electroretinogram (ERG). The rats were divided into four groups: intact control group (INT), diabetic retinopathy group (DR), DR group with subconjunctival MSC injection (DR-MSC), and DR group with subconjunctival sirolimus-pretreated MSC injection (DR-MSC-S). The effects of transplantation were evaluated using ERG and histological examinations. RESULTS: The ERG results showed that the DR-MSC-S group did not significantly differ from the INT in b-wave amplitude and exhibited significantly higher values than the DR-MSC and DR groups (p < 0.01). The flicker amplitude results showed that the DR-MSC and DR-MSC-S groups had significantly higher values than the DR group (p < 0.01). Histological examination revealed that the retinal layers were thinner in the DR-induced groups compared to the INT group, with the DR-MSC-S group showing the thickest retinal layers among them. CONCLUSIONS: Subconjunctival injection of sirolimus-pretreated MSCs can enhance retinal function and mitigate histological changes in the STZ-induced DR rat model.

Comparison between arthroscopic suture anchor fixation and open plate fixation in the greater tuberosity fracture of the proximal humerus.

INTRODUCTION: The purpose of this study is to compare the clinical and radiological outcomes of patients undergoing open reduction and internal fixation (OR/IF) using a plate or patients undergoing an arthroscopic suture anchor fixation for the greater tuberosity (GT) fracture of the proximal humerus. The purpose of this study is to compare the clinical and radiological outcomes of patients undergoing OR/IF or an arthroscopic suture anchor fixation for the GT fracture. MATERIALS AND METHODS: Between January, 2010 and December, 2020, 122 patients with GT fracture underwent operative fixation. Either OR/IF using proximal humeral locking plate (50 patients) or arthroscopic suture anchor (72 patients) fixation was performed. Fourteen patients were lost to follow-up and finally, 108 patients were enrolled in this study. We divided these patients into two groups: (1) OR/IF group (Group I: 44 patients) and arthroscopic anchor fixation group (Group II: 64 patients). The primary outcome was subjective shoulder function (shoulder functional scale). Secondary outcomes were range of motion, and complications including GT fixation failure, fracture migration, or neurologic complication. Also, age, sex, BMI, operation time, shoulder dislocation, fracture comminution, AP (anteroposterior), SI (superoinferior) size and displacement were evaluated and compared between two groups. RESULTS: Both groups showed satisfactory clinical and radiological outcomes at mid-term follow-up. Between 2 groups, there were no significant differences in age, sex, BMI, presence of shoulder dislocation or comminution. Group II showed higher clinical scores except VAS score (p < 0.05) and longer surgical times (95.3 vs. 61.5 min). Largest fracture displacement (Group I vs. II: SI displacement: 40 vs. 13 mm, and AP displacement: 49 vs. 11 mm) and higher complication rate (p = 0.049) was found in Group I. CONCLUSIONS: Both arthroscopic anchor fixation and open plate fixation methods showed satisfactory outcomes at mid-term follow-up. Among them, OR/IF is preferred for larger fracture displacement (> 5 mm) and shorter operation time However, arthroscopic anchor fixation group showed better clinical outcomes and less complications than the OR/IF group. LEVEL OF EVIDENCE: Level 4, Case series with subgroup analysis.

Therapeutic role of 2-stearoxyphenethyl phosphocholine targeting microtubule dynamics and Wnt/ß-catenin/EMT signaling in human colorectal cancer cells.

The inhibition of cell death, perturbation of microtubule dynamics, and acceleration of Wnt/ß-catenin/epithelial-mesenchymal transition (EMT) signaling are fundamental processes in the progression and metastasis of colorectal cancer (CRC). To explore the role of 2-stearoxyphenethyl phosphocholine (stPEPC), an alkylphospholipid-based compound, in CRC, we conducted an MTT assay, cell cycle analysis, western blot analysis, immunoprecipitation, immunofluorescence staining, Annexin V/propidium iodide double staining, small interfering RNA gene silencing, a wound-healing assay, an invasion assay, and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay in the human CRC cell lines HT29 and HCT116. stPEPC showed anti-proliferative properties and mitotic cell accumulation via upregulated phosphorylation of BUBR1 and an association between mitotic arrest deficiency 2 (MAD2) and cell division cycle protein 20 homolog (CDC20). These results suggest that activation of the mitotic checkpoint complex and tubulin polymerization occurred, resulting in mitotic catastrophe in HT29 and HCT116 cells. In addition, stPEPC attenuated cell migration and invasion by regulating proteins mediated by EMT, such as E-cadherin and occludin. stPEPC altered the protein expression of Wnt3a and phosphorylation of low-density lipoprotein receptor-related protein 6 (LRP6), glycogen synthase kinase 3ß (GSK3ß), and ß-catenin as well as their target genes, including cMyc and cyclin D1, in CRC cells. Thus, stPEPC may be useful for developing new drugs to treat human CRC.

Evaluation of ciliary cleft changes after phacoemulsification using ultrasound biomicroscopy in dogs with cataracts.

Introduction: Glaucoma is one of the most serious complications that causes irreversible blindness after phacoemulsification in dogs; however, a clear mechanism has not been elucidated. This study aimed to analyse the possible anatomical factors associated with glaucoma after phacoemulsification using parameters that reflect the anatomical characteristics of dogs. Materials and methods: A total of 69 eyes of 48 dogs were included in this study. The patients were divided into three groups: normal eye (n = 18), cataract (n = 39), and post-phacoemulsification for at least 2 months after surgery (post-phaco, n = 12). For further analysis, the dogs were subdivided into two groups according to cataract stage: phacoemulsification non-candidate and candidate groups. Non-cataracts and incipient cataracts were categorized into the non-candidate group, whereas immature and mature cataracts were categorized into the candidate group. Measurements of the ciliary cleft parameters, including the area of the ciliary cleft (CCA), length of the ciliary cleft (CCL), width of the ciliary cleft (CCW), iridocorneal angle, and angle opening distance, were obtained using ultrasound biomicroscopy. Results: CCA, CCL, and CCW were significantly higher in the candidate group than in the non-candidate group. CCA, CCL, and CCW were significantly reduced in the post-phaco group compared to those in the cataract group. Based on these results, we found that the ciliary cleft expanded in cataract-affected eyes and narrowed after phacoemulsification. This may indicate that the space between the trabecular meshworks became narrower, potentially leading to an increase in the resistance of the aqueous humor. Conclusion: A narrowed ciliary cleft after phacoemulsification may be an anatomical factor associated with glaucoma.

Comprehensive Lipid Profiling Recapitulates Enhanced Lipolysis and Fatty Acid Metabolism in Intimal Foamy Macrophages From Murine Atherosclerotic Aorta.

Lipid accumulation in macrophages is a prominent phenomenon observed in atherosclerosis. Previously, intimal foamy macrophages (FM) showed decreased inflammatory gene expression compared to intimal non-foamy macrophages (NFM). Since reprogramming of lipid metabolism in macrophages affects immunological functions, lipid profiling of intimal macrophages appears to be important for understanding the phenotypic changes of macrophages in atherosclerotic lesions. While lipidomic analysis has been performed in atherosclerotic aortic tissues and cultured macrophages, direct lipid profiling has not been performed in primary aortic macrophages from atherosclerotic aortas. We utilized nanoflow ultrahigh-performance liquid chromatography-tandem mass spectrometry to provide comprehensive lipid profiles of intimal non-foamy and foamy macrophages and adventitial macrophages from Ldlr-/- mouse aortas. We also analyzed the gene expression of each macrophage type related to lipid metabolism. FM showed increased levels of fatty acids, cholesterol esters, phosphatidylcholine, lysophosphatidylcholine, phosphatidylinositol, and sphingomyelin. However, phosphatidylethanolamine, phosphatidic acid, and ceramide levels were decreased in FM compared to those in NFM. Interestingly, FM showed decreased triacylglycerol (TG) levels. Expressions of lipolysis-related genes including Pnpla2 and Lpl were markedly increased but expressions of Lpin2 and Dgat1 related to TG synthesis were decreased in FM. Analysis of transcriptome and lipidome data revealed differences in the regulation of each lipid metabolic pathway in aortic macrophages. These comprehensive lipidomic data could clarify the phenotypes of macrophages in the atherosclerotic aorta.

Preventive Effects of Exosome-Rich Conditioned Medium From Amniotic Membrane-Derived Mesenchymal Stem Cells for Diabetic Retinopathy in Rats.

Purpose: Diabetic retinopathy (DR) is an important disease that causes vision loss in many diabetic patients. Stem cell therapy has been attempted for treatment of this disease; however, it has some limitations. This study aimed to evaluate the preventive efficacy of exosome-rich conditioned medium (ERCM) derived from amniotic membrane stem cells for DR in rats. Methods: Twenty-eight 8-week-old male Sprague-Dawley rats were divided into three groups: group 1, normal control (Con) group; group 2, diabetes mellitus (DM) group; and group 3, DM with ERCM-treated (DM-ERCM) group. DM was induced by intraperitoneal injection of streptozotocin. The DM-ERCM group received ERCM containing 1.2 × 109 exosomes into subconjunctival a total of four times every 2 weeks. Results: On electroretinogram, the DM-ERCM group had significantly higher b-wave and flicker amplitudes than those in the DM group. In fundoscopy, retinal vascular attenuation was found in both the DM and DM-ERCM groups; however, was more severe in the DM group. On histology, the ganglion cell and nerve fiber layer rates of the total retinal layer significantly increased in the DM group compared with the Con group, whereas the DM-ERCM group showed no significant difference compared with the Con group. Cataracts progressed significantly more in the DM group than that in the DM-ERCM group and there was no uveitis in the DM-ERCM group. Conclusions: Subconjunctival ERCM delayed the progression of DR and cataracts and significantly reduced the incidence of uveitis. Translational Relevance: Our study shows the clinical potential of minimally invasive exosome-rich conditioned medium treatment to prevent diabetic retinopathy.

Metallosis-Induced Conversion Shoulder Arthroplasty: A Unique Experience and Literature Review.

BACKGROUND: Total shoulder arthroplasty (TSA) can fail for several reasons, such as component loosening, periprosthetic fracture, instability, infection, soft tissue failure, or joint overstuffing. Severe metallosis without loose glenoid components after TSA may result in the need for revision to reverse TSA. CASE PRESENTATION: Four years before the current presentation, an 86-year-old woman suffered from right shoulder pain and swelling. The initial diagnosis was osteoarthritis of the shoulder joint, for which she underwent TSA. Four years later, she complained of shoulder joint pain, swelling, and limited range of motion. On sonography, subscapularis and supraspinatus tendon tears were identified. Plain radiographs and computed tomography (CT) scans showed metallosis around the shoulder joint. Due to the rocking horse mechanism, wear of the upper portion of the glenoid component and bearing caused a foreign-body reaction and severe metallosis around the joint. Due to a massive rotator cuff tear combined with glenoid component wear, the patient eventually underwent reverse TSA (RTSA) and was satisfied with the final results. CONCLUSIONS: Severe metallosis due to glenoid component wear combined with a massive rotator cuff tear in TSA may cause the need for revision to RTSA.

Soft tissue pseudotumors of the hand and wrist mimicking malignancy: Two case reports.

RATIONALE: Most soft-tissue lesions in the hand and wrist have a benign etiology, and malignant tumors, such as soft-tissue sarcomas, are rare. Mimickers of soft tissue tumors in the hand and wrist are more common than true neoplastic lesions; however, soft tissue pseudotumors that mimic malignancy are very rare. PATIENT CONCERNS: This study describes 2 patients with soft tissue pseudotumors of the hand and wrist. Both patients presented with rapidly growing soft-tissue masses. Magnetic resonance imaging (MRI) revealed ill-defined margins and an aggressive appearance in both cases, leading to a strong suspicion of malignant soft tissue tumors. DIAGNOSIS: Both patients underwent incisional biopsies, and the final diagnoses were inflammation due to IgG4-related disease in the first case and chronic granulomatous inflammation in the second case. INTERVENTIONS: The first patient was administered oral steroids, while the second patient was treated with anti-inflammatory drugs. OUTCOMES: Both patients showed a reduction in swelling of the hand and wrist. LESSONS: Although the imaging approach for pseudotumorous lesions is similar to that for true soft tissue tumors, the management of these lesions is different. Biopsies should only be performed when the diagnosis is unclear.

Design, synthesis, and study of novel phenethyl-based antitumor phospholipids downregulating p38 mitogen-activated protein kinase.

Phenethyl-based edelfosine-analogs with saturated, monounsaturated, or polyunsaturated alkoxy substituents on phenyl ring were designed as novel antitumor lipids modulating p38 MAPK. Evaluation of the synthesised compounds against nine panels of diverse cancer cells presented saturated and monounsaturated alkoxy-substituted derivatives as the most active than other derivatives. In addition, ortho-substituted compounds were more active than meta- or ortho-substituted compounds. They were potential anticancer agents against blood, lung, colon, CNS, ovary, renal, and prostate cancers but not against skin nor breast cancers. Compounds, 1b and 1a emerged as the most potential anticancer agents. Assessment of compound 1b impact on p38 MAPK and AKT confirmed it as an inhibitor of p38 MAPK but not AKT. In silico study suggested compounds 1b and 1a as possible binders to the lipid binding pocket of p38 MAPK. Overall, compounds 1b and 1a as novel broad spectrum antitumor lipids modulating activity of p38 MAPK for further development.

Mid-term comparative study between the glenoid and humerus lateralization designs for reverse total shoulder arthroplasty: which lateralization design is better?

INTRODUCTION: The complications of the conventional medialized design for reverse total shoulder arthroplasty (RSA) are increased scapular notching, and decreased external rotation and deltoid wrapping. Currently, lateralization design RSA, which avoid scapular notching and improve impingement-free range of motion, is commonly used. Especially, humeral lateralization design was most commonly used and glenoid lateralization design was preferred for glenoid abnormities. We compared mid-term clinical and radiologic outcomes of glenoid and humeral lateralization RSA in an Asian population in this study. MATERIALS AND METHODS: We enrolled 124 shoulders of 122 consecutive patients (mean age 73.8 ± 6.8 years) who received glenoid or humeral lateralization RSA from May, 2012 to March, 2019. We divided these patients into two groups according to RSA using either glenoid or humeral lateralization design. These different designs were introduced consecutively in Korea. The clinical and radiological results of 60 glenoid lateralization RSA (Group I, 60 patients) and 64 humeral lateralization RSA (Group II, 62 patients) were retrospectively evaluated and also were compared between the two groups. All patients were followed for mean 3 years. RESULTS: The clinical and radiologic outcomes of the two groups did not differ significantly, including scapular notching (p = 0.134). However, humeral lateralization RSA showed a larger glenoid-tuberosity (GT) distance (p = 0.000) and less distalization shoulder angle (DSA) (p = 0.035). The complication rate did not differ significantly either. But, revision surgery was performed for 2 humeral loosening in the Group II. CONCLUSION: The clinical and radiologic outcomes of the two groups did not differ significantly, including scapular notching at mid-term follow-up. However, humeral lateralization design showed larger GT distance and less DSA. Humeral lateralization design RSA could preserve the normal shoulder contour due to a larger GT distance (more lateralization) and provide less deltoid tension due to less DSA (less distalization of COR).

siRNAs to Knockdown Antiviral Chemokine-related Genes in FRhK-4 Cells.

The objective of this study was to generate small interfering RNA (siRNA) to knockdown antiviral chemokine-related genes in fetal rhesus monkey kidney (FRhK-4) cells. We generated siRNA duplexes to suppress antiviral chemokines like CXCL10 and CCL4 in FRhK-4 cells by downregulating interferon regulatory factor (IRF) 3 and IRF7. Three siRNA duplexes (si-F-IRF3-1, si-F-IRF3-2, and si-F-IRF3-3) targeting IRF3, and one siRNA duplex (si-F-IRF7) targeting IRF7 were generated. A nontarget siRNA duplex was used as the negative control. The nontarget or target siRNA duplexes (si-F-IRF3-1, si-F-IRF3-2, si-F-IRF3-3, and si-F-IRF7) were transfected into FRhK-4 cells using transfection reagents, and they were then incubated at 37°C for 6 h with 5% CO2. After 6 h, the medium was removed, and fresh medium was added to each cell, and they were then incubated at 37°C for 48 h with 5% CO2. The transfected FRhK-4 cells were infected with hepatitis A virus (HAV) HM-175/18f (viral titer: 105 PFU/mL) and incubated at 37°C for 3 h with 5% CO2 for HAV propagation. The expression levels of chemokines, including CXCL10 and CCL4, under the regulation of IRF3 and IRF7 in the transfected FRhK-4 cells were measured using quantitative real-time polymerase chain reaction after 3 h of HAV infection. The results indicated that CXCL10 and CCL4 expression levels were decreased in FRhK-4 cells transfected with si-F-IRF3-1, si-F-IRF3-3, or si-F-IRF7 (p < 0.05) compared to those in the negative control. These results indicate that si-F-IRF3-1 and si-F-IRF3-3, and si-F-IRF7 successfully knocked down IRF3 and IRF7 in FRhK-4 cells, respectively and suppressed antiviral chemokines. These siRNAs could be used to suppress antiviral chemokines in FRhK-4 cells.

Comment on Billant et al. p53, A Victim of the Prion Fashion. Cancers 2021, 13, 269.

The p53 tumor suppressor is a central protein in the fight against cancer [...].

Comparisons between treatment of isolated posterosuperior paralabral cysts and simultaneous treatment of cysts combined with associated shoulder pathologies: arthroscopic treatment of posterosuperior paralabral cysts.

INTRODUCTION: The purpose of this study is to report the radiologic and clinical outcomes of arthroscopic intervention for isolated posterosuperior paralabral cysts and simultaneous treatment of cysts combined with associated shoulder pathologies. MATERIALS AND METHODS: From March 2008 through December 2016, 70 cases (48 males and 22 females) operated on for symptomatic posterosuperior paralabral cysts were included. Mean age was 45 (range 18-69). These patients were classified into two groups depending on if they had accompanying lesions: Group I (isolated group, 27 patients) and Group II (concomitant group, 43 patients). Arthroscopic cyst decompression with a labral repair or posterior capsulotomy for patients without labral tear were performed. All concomitant pathologies were also operated simultaneously. Follow-up MRI were performed at postoperative 6 months and clinical outcomes were evaluated during the follow-up. RESULTS: Arthroscopic all intra-articular cyst decompression and labral repair was performed on 67 patients. In three patients, posterior capsulotomy without labral repair was performed for cyst removal. For 43 patients with concomitant lesions, 31 rotator cuff repairs, three SLAP repairs along with biceps tenodesis, two distal clavicle resections due to A-C joint arthritis, one calcific deposit removal, four Bankart repairs, and two acromioplasties were performed. The follow-up MRI showed complete cyst resorption except for two patients. The mean VAS, ASES, UCLA, SST and CS scores significantly improved at the last follow-up. Although both groups showed significantly improved range of motion after the surgery, improvement of ROM in Group II lagged at early periods of the rehabilitation. CONCLUSIONS: Arthroscopic labral repair with all intra-articular cysts decompression or simple posterior capsulotomy were both effective treatment modalities. If paralabral cysts were associated with other shoulder lesions, simultaneous treatment of combined lesions could be performed for the improved clinical outcomes at final follow-up with expected lag in the early rehabilitation period. LEVEL OF EVIDENCE: Level III, Retrospective Comparative Trial, Treatment Study.